History
When evaluation a patient with what appears to be a dystonic syndrome, the following history should be documented:
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Age of onset
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Initial site of involvement and progression to other body sites and time course of progression
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Occurrence of dystonia at rest, with any specific voluntary action, or posture maintenance
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Presence or absence of tremor or other movement disorders
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Presence or absence of a sensory trick, or geste antagoniste [52]
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A family history of similar symptoms or other involuntary movements, the age of onset of similar symptoms, and body part predominantly affected
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Previous therapeutic trial and response to low-dose levodopa, to exclude dopamine-responsive dystonia
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Any secondary etiologies, such as trauma, infectious process, birth injury, or developmental delay
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Exposure to any medications reported to cause dystonia, such as levodopa, dopamine agonists, antipsychotics, neuroleptics, dopamine-blocking agents, metoclopramide, fenfluramine, flecainide, ergot agents, anticonvulsive agents, and certain calcium channel blockers
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Other complaints associated with the dystonic symptoms
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Pain, which is not usually a prominent feature except in some cases of cervical dystonia and other forms of secondary dystonia (eg, reflex sympathetic dystrophy and foot dystonia occurring with Parkinson disease)
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Aggravating or attenuating factors
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Degree of functional impairment resulting from the dystonia
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Additional questions about the following may help in determining if dystonia is affecting other body parts (such involvement might not be otherwise volunteered):
Increased blinking
Intermittent puckering of the mouth
Chewing movements
Tongue popping
Stuttering
Difficulty speaking
Becoming breathless when speaking with a soft voice
Turning, tilting, or shifting of the head in any direction
Jerking of the head
Twisting of the body
Tremors of the hands or feet, arms, or legs
Twisting or moving involuntarily when using hands or walking
Difficulty with writing
History of clumsiness
Cramps when using the hands or legs
Toes going up or down involuntarily or being pigeon toed
Physical
It is important to note the distribution of body parts affected. Although classification of the distribution is arbitrary, it may serve as a useful guide in clinical practice and may help in grouping families and patients for clinical trials and genetic studies.
Distributions are classified as follows:
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Focal (single body region)
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Segmental (2 or more contiguous regions)
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Multifocal (2 or more noncontiguous regions)
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Hemidystonia (involving one side of the body)
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Generalized (leg, trunk, and one other region or both legs with or without trunk involvement plus 1 other region)
The central features that distinguish dystonia from other involuntary movement disorders are the posture-assuming features or directional quality and patterned predictable involvement of a specific set of muscles involved.
Although the pattern of muscle contractions in dystonia is consistent and predictable, involuntary movements vary with changing postures or tasks.
The site of involvement may remain focal or progress to involve other parts of the body over time.
The speed of dystonic contractions may be rapid or slow.
Various sensory tricks may be performed that diminish the dystonic movements, termed geste antagoniste.
Dystonic movements intensify with voluntary action. Movements of primary dystonia commonly occur with specific actions and are not present at rest. As the dystonic condition progresses, relatively nonspecific voluntary actions can bring out the dystonic movements. With still further worsening, the affected limb can develop dystonic movements while at rest, and the patient eventually develops sustained posturing.
Irregular, rhythmic contractions termed dystonia tremors may be observed. The tremor is irregular compared to the tremor seen in essential tremor.
Facial muscles are affected, as manifested by patterned and sustained contractions of the forehead, eyelids, and lower face. Limbs may be affected as well, and specific voluntary tasks may intensify such contractions. Examples are writing when the upper extremities are affected and walking forward but not backward when lower extremities are affected.
It is important to note other physical and abnormal neurologic findings in addition to the dystonia.
Causes
Dystonia has historically been classified into 2 main etiologic groups: primary (idiopathic) and secondary (symptomatic). [1] Idiopathic dystonia was distinguished from the symptomatic dystonias both by its lack of known cause and the absence of consistent brain pathology. However, it has become clearer that idiopathic dystonia consists of a group of clinical syndromes that are likely to have a genetic basis. Primary dystonia is a genetically heterogeneous disease. [17, 18] . Currently, 25 DYT loci are recognized and dystonia forms are labeled DYT in the order they were discovered; 20 are inherited as autosomal dominant, 4 are inherited as autosomal recessive, and 1 (dystonia parkinsonism) is an X-linked recessive trait. [19, 51]
Table 2 below lists the genetic loci for dystonia.
Table. (Open Table in a new window)
| Type | Designation | Mode of Inheritance | Gene | Gene Locus | OMIM# |
|---|---|---|---|---|---|
DYT1 |
Early-onset generalized | Autosomal dominant | TOR1A | 9q.34.11 | 128100 |
| DYT2 | Early-onset generalized | Autosomal recessive | Uknown | Uknown | 224500 |
| DYT3 | X-linked dystonia parkinsonism (Lubag syndrome) | X-chromosomal recessive | TAF1 | Xq13.1 | 314250 |
| DYT4 | Torsion dystonia (Whispering dysphonia) | Autosomal dominant | TUBB4A | 19p13.3 | 128101 |
| DYT5a | Dopa-responsive dystonia (Segawa disease) | Autosomal dominant | GCH1 | 14q22.1–22.2 | 128230 |
| DYT5b | Dopa-responsive dystonia | Autosomal recessive | TH | 11p15.5 | 605407 |
| DYT6 | Adolescent-onset mixed phenotype | Autosomal dominant | THAP1 | 8p11.21 | 602629 |
| DYT7 | Paroxysmal dystonic choreoathetosis | Autosomal dominant | Unknown | 18p | 602124 |
| DYT8 | Paroxysmal kinesigenic, nonkinesigenic dyskinesia | Autosomal dominant | MR-1 | 2q33–35 | 118800 |
| DYT9 | Paroxysmal choreoathetosis with spasticity | Autosomal dominant | CSE | 1p | 601042 |
| DYT10 | Paroxysmal kinesigenic dystonia | Autosomal dominant | PRRT2 | 16q11.2–12.1 | 128200 |
| DYT11 | Myoclonus dystonia | Autosomal dominant | SGCE | 7q21.3 | 159900 |
| DYT11 | Myoclonus dystonia | Autosomal dominant | DRD2 | 11q23.2 | 159900 |
| DYT12 | Rapid-onset dystonia parkinsonism (syndrome) | Autosomal dominant | ATP1A3 | 19q12–13.2 | 128235 |
| DYT13 | Early- and late-onset focal or craniocervical dystonia | Autosomal dominant | Unknown | 1p36.32-p36.13 | 607671 |
| DYT14 | Dopa-responsive generalized dystonia | ||||
| DYT15 | Myoclonus-dystonia | Autosomal dominant | Unknown | 18p11 | 607488 |
| DYT16 | Dystonia-parkinsonism syndrome | Autosomal recessive | PRKRA | 2q31.2 | 612067 |
| DYT17 | Adolescent onset | Autosomal recessive | Unknown | 20p11.2-q13.12 | 612406 |
| DYT18 | Paroxysmal exertion-induced dyskinesia | Autosomal dominant | SLC2A1 | 1p34.2 | 612126 |
| DYT19 | Paroxysmal kinesigenic dyskinesia 2 | Autosomal dominant | Unknown | 16q13-q22.1 | 611031 |
| DYT20 | Paroxysmal nonkinesigenic dyskinesia 2 | Autosomal dominant | Unknown | 2q31 | 611147 |
| DYT21 | Late-onset torsion dystonia | Autosomal dominant | Unknown | 2q14.3-q21.3 | 614588 |
| DYT22 | Unknown | Unknown | Not listed | ||
| DYT23 | Adult-onset cervical dystonia | Autosomal dominant | CIZ1 | 9q34 | 614860 |
| DYT24 | Focal dystonia | Autosomal dominant | ANO3 | 11p14.2 | 615034 |
| DYT25 | Adult-onset focal dystonia | Autosomal dominant | GNAL | 18p11.21 | 615073 |
Table. (Open Table in a new window)
Primary dystonia
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Idiopathic or primary torsion dystonia: Despite a negative family history, a genetic basis for dystonia is not ruled out completely, as its mode of inheritance is usually autosomal dominant with incomplete penetrance.
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Sporadic and familial torsion dystonia (various genetic forms; see Table 2)
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Inherited (ie, hereditary) dystonia (various genetic forms; see Table 2)
Secondary dystonia
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Vascular
Cerebrovascular, or ischemic injury
Perinatal cerebral injury
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Infectious
Subacute sclerosing panencephalitis
Trauma
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Head trauma
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Peripheral trauma
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Space-occupying lesions in the brain
Drugs
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Levodopa, dopamine agonists, antipsychotics, metoclopramide, fenfluramine, flecainide, ergot agents, anticonvulsant agents, certain calcium channel blockers
Toxins
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Manganese, carbon monoxide, carbon disulfide, methanol, disulfiram, wasp sting
Metabolic conditions
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Kernicterus
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Amino acid disorders
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Glutaric acidemia
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Methylmalonic acidemia
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Homocystinuria
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Hartnup disease
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Tyrosinosis
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Lipid disorders
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Metachromatic leukodystrophy
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Neuronal ceroid lipofuscinosis
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Dystonic lipidoses - Niemann-Pick disease, type C (ie, sea blue histiocytosis)
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Primary antiphospholipid antibody syndrome
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Gangliosidoses (ie, GM1, GM2)
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Mitochondrial encephalopathies (eg, Leigh disease, Leber disease)
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Lesch-Nyhan syndrome
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Triosephosphate isomerase deficiency [26]
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Vitamin E deficiency
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Biopterin deficiency
Genetic factors
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Dystonia plus syndromes
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Myoclonus dystonia
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Dopa-responsive dystonia (DRD)
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Rapid-onset dystonia parkinsonism
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Lubag or X-linked dystonia parkinsonism
Neurodegenerative conditions
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Hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration (HARP) syndrome
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Spinocerebellar ataxia (SCA), types 1, 2, or 3
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Ataxia telangiectasia
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Dentatorubropalidoluysian atrophy
Demyelination
Other structural conditions
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Atlantoaxial subluxation
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Arnold-Chiari malformation
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Congenital Klippel-Feil syndrome
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Idiopathic torsion dystonia. Major nuclear complex of the basal ganglia is the striatum, which is composed of the caudate and putamen. The striatum receives glutamatergic input from the cerebral cortex and dopaminergic input from the substantia nigra pars compacta (SNc). Two types of spiny projection neurons receive cortical and nigral inputs: those that project directly and those that project indirectly to the internal segment of the globus pallidus (GPI), which is the major output site of the basal ganglia. Complementary action of both of these pathways regulates the overall function of the GPI. The GPI, which, in turn, provides tonic inhibitory (ie, gamma-aminobutyric acid [GABA]–ergic) discharges downstream into the thalamic nuclei that project to the frontal cortical and other CNS areas. Direct pathway (D1) inhibits the substantia nigra pars reticulata (SNr) and the GPI, which are the major output sites, resulting in a net disinhibition and facilitation of thalamocortical circuits. Indirect pathway (D2), through serial connections with the globus pallidus pars externa (GPe) and the subthalamic nucleus (STN), is excitatory to the GPI, resulting in further inhibitory action on thalamocortical pathways. In this model, the mean discharge rate of the GPI is the key factor that determines a hypokinetic or hyperkinetic movement disorder. Increased inhibitory influences of the GPI on the thalamocortical circuitry result in hypokinetic disorders, such as Parkinson disease, whereas decreased GPI activity results in hyperkinetic disorders, such as hemiballismus. VL = ventrolateral thalamus.
Tables
Focal |
Body Site |
Segmental |
two or more contiguous body regions |
Multifocal |
two or more noncontiguous body regions |
Generalized |
involving atleast one leg, the trunk and another body region |
Hemidystonia |
involving one side of the body |
| Type | Designation | Mode of Inheritance | Gene | Gene Locus | OMIM# |
|---|---|---|---|---|---|
DYT1 |
Early-onset generalized | Autosomal dominant | TOR1A | 9q.34.11 | 128100 |
| DYT2 | Early-onset generalized | Autosomal recessive | Uknown | Uknown | 224500 |
| DYT3 | X-linked dystonia parkinsonism (Lubag syndrome) | X-chromosomal recessive | TAF1 | Xq13.1 | 314250 |
| DYT4 | Torsion dystonia (Whispering dysphonia) | Autosomal dominant | TUBB4A | 19p13.3 | 128101 |
| DYT5a | Dopa-responsive dystonia (Segawa disease) | Autosomal dominant | GCH1 | 14q22.1–22.2 | 128230 |
| DYT5b | Dopa-responsive dystonia | Autosomal recessive | TH | 11p15.5 | 605407 |
| DYT6 | Adolescent-onset mixed phenotype | Autosomal dominant | THAP1 | 8p11.21 | 602629 |
| DYT7 | Paroxysmal dystonic choreoathetosis | Autosomal dominant | Unknown | 18p | 602124 |
| DYT8 | Paroxysmal kinesigenic, nonkinesigenic dyskinesia | Autosomal dominant | MR-1 | 2q33–35 | 118800 |
| DYT9 | Paroxysmal choreoathetosis with spasticity | Autosomal dominant | CSE | 1p | 601042 |
| DYT10 | Paroxysmal kinesigenic dystonia | Autosomal dominant | PRRT2 | 16q11.2–12.1 | 128200 |
| DYT11 | Myoclonus dystonia | Autosomal dominant | SGCE | 7q21.3 | 159900 |
| DYT11 | Myoclonus dystonia | Autosomal dominant | DRD2 | 11q23.2 | 159900 |
| DYT12 | Rapid-onset dystonia parkinsonism (syndrome) | Autosomal dominant | ATP1A3 | 19q12–13.2 | 128235 |
| DYT13 | Early- and late-onset focal or craniocervical dystonia | Autosomal dominant | Unknown | 1p36.32-p36.13 | 607671 |
| DYT14 | Dopa-responsive generalized dystonia | ||||
| DYT15 | Myoclonus-dystonia | Autosomal dominant | Unknown | 18p11 | 607488 |
| DYT16 | Dystonia-parkinsonism syndrome | Autosomal recessive | PRKRA | 2q31.2 | 612067 |
| DYT17 | Adolescent onset | Autosomal recessive | Unknown | 20p11.2-q13.12 | 612406 |
| DYT18 | Paroxysmal exertion-induced dyskinesia | Autosomal dominant | SLC2A1 | 1p34.2 | 612126 |
| DYT19 | Paroxysmal kinesigenic dyskinesia 2 | Autosomal dominant | Unknown | 16q13-q22.1 | 611031 |
| DYT20 | Paroxysmal nonkinesigenic dyskinesia 2 | Autosomal dominant | Unknown | 2q31 | 611147 |
| DYT21 | Late-onset torsion dystonia | Autosomal dominant | Unknown | 2q14.3-q21.3 | 614588 |
| DYT22 | Unknown | Unknown | Not listed | ||
| DYT23 | Adult-onset cervical dystonia | Autosomal dominant | CIZ1 | 9q34 | 614860 |
| DYT24 | Focal dystonia | Autosomal dominant | ANO3 | 11p14.2 | 615034 |
| DYT25 | Adult-onset focal dystonia | Autosomal dominant | GNAL | 18p11.21 | 615073 |
